1. Field of the Invention
The present invention relates to carbapenem antibiotics and, more particularly, to 1.beta.-methyl-carbapenem derivatives having a methyl group introduced at the 1-position and [1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio group introduced at the 2-position of the carbapenem skeleton, and to antibacterial compositions containing the same as an active ingredient.
2. Description of the Prior Art
Prior art antibacterial carbapenems including carba-2-formula (A): ##STR2##
For example, an initial generation of carbapenem antibiotics is a naturally occurring carbapenem compound such as thienamycin represented by the formula (B): ##STR3##
The thienamycin may be obtained from a fermentation broth of Streptomyces cattleya and has a broad range of antibacterial spectra against Gram-positive and Gram-negative bacteria. A prior art compound is imipenem (INN) represented by the following formula (C): ##STR4## This compound is a practically available antibacterial agent and may be obtained by converting an amino group as a side chain at the 2-position to a formimidoyl group.
The imipenem of the formula (C) exhibits antibacterial activities higher than those of the thienamycin and ensures some degree of chemical stability; however, it presents the disadvantage that it is decomposed within a short period of time by kidney dehydropeptidase (DHP) in the living body. For this reason, it cannot be administered singly, and must be used in combination with a DHP inhibitor in order to control its decomposition leading to inactivation. Its formulation for clinical administration is a combination with cilastatin (INN) that is a DHP inhibitor.
An antibacterial agent preferred for practical clinical use, however, is one that alone can demonstrate antibacterial activity. Furthermore, the DHP inhibitor to be combined with the antibiotic could exert undesirable actions on tissues of the living body. For these reasons, a combined use should be avoided wherever possible. Thus there has been a growing demand for a carbapenem compound having sufficiently high degrees of both antibacterial activity and resistance to DHP.
Recently, there were proposed some carbapenem compounds of the type that could achieve the above objectives. Such carbapenem compounds are 1-methyl-carbapenem compounds in which a methyl group is introduced at the 1-position and various heterocyclyl-thio groups at the 2-position of the carbapenem skeleton. For example, Japanese Laid-Open Patent Publication No. 202,866/1985 to Sankyo discloses 2-heterocyclyl-thio-1-methylcarbapenem compounds including a compound having at the 2-position a (N-methylacetoimidoyl-azetidin-3-yl)thio substituent, represented by the formula (D): ##STR5## It is reported that this compound has superior antibacterial activities as well as a remarkably improved resistance to decomposition by DHP leading to inactivation so that it demonstrates highly useful effects; however, the Japanese Patent document does not provide any specific antibacterial data or working examples. Therefore, Sankyo does not disclose anything about carbapenem compounds having at the 2-position 1-(1,3-thiazolin-2-yl)-azetidin-3-yl-thio substituent according to the present invention. Most recently, International Patent Publication Number WO 93/23,402 to Fujisawa disclosed 2-(3-azetidinylthio) carbapenem compounds represented by the following formula (E): ##STR6##
The Fujisawa patent publication has a general disclosure of compounds of the formula (F): ##STR7## wherein R.sup.4 and R.sup.5 are combined together to form optionally substituted imino-containing heterocyclic group.
Christensen et al. European published application 0 161 541 is also cited to show the state of the art.
Carbapenem compounds possess a potent antibacterial activity with a broad spectrum. However, like other .beta.-lactam antibacterial agents used in clinical practice, it is anticipated that carbapenem compounds will be uneffective against carbapenem-resistant bacteria. Accordingly, there have been proposed some carbapenem compounds having unique substituents at 2-position of the carbapenem skeleton. Furthermore, even though oral formulations of carbapenem compounds are useful for daily administration, the carbapenem antibiotics which have been proposed in prior patent application are mainly used for injectable formulation. Therefore, there has been a demand for orally administrable carbapenem antibiotics.